Professor of Pediatric Infectious Diseases and Laboratory Medicine; Co-Director of Pediatric Infectious Diseases Virology Clinic. Our research focuses on practical questions related to the prevention of HIV-1 infection in infants, mechanisms leading to shedding of virus in breast milk and genital tract of adults, treatment of drug-resistant virus in children and adults, and understanding mechanisms leading to the persistence of HIV infection.

Over the past 20 years, our group has conducted projects in Peru, Thailand, Mozambique, Kenya and South Africa. These studies aimed to better understand the transmission, selection and persistence of drug-resistant viruses and have included collaborations with other UW, national and international investigators. We have developed economical assays with the goal of making testing accessible to resource-poor communities, to improve the management of HIV infection. Currently, our laboratory located within Seattle Childrens Research Institute (SCRI) focuses primarily on three topics and collaborates broadly with other UW, national and international investigators.

1. Persistence of HIV infection: A major research focus of our work has been to understand the mechanisms that allow HIV to persist despite effective ART. Our group documented that among ART-treated individuals with plasma HIV RNA consistently below the limits of detection included a subset that demonstrated viral evolution, implying low-level viral replication, although the vast majority demonstrated no evolution (Frenkel, JVI, 2003). We were the first to note that transient low-level viremias, or "blips," during ART were usually comprised of populations of identical env and pol sequences (Tobin, JVI, 2005), suggesting production of clonal virus. Our subsequent studies revealed that populations of identical viral sequences in PBMC and sputum (rich in pulmonary macrophages) increase over a decade of ART (Wagner, JVI, 2013), suggesting that clonal proliferation of cells with provirus sustains HIV infection during suppressive ART. Recently, we have documented that identical env sequences have identical integration sites, providing strong supportive evidence that HIV persistence is at least in part due to cellular proliferation, and with ongoing suppressive ART, that these proviruses are increasingly integrated into genes controlling immune functions, the cell cycle or cancers suggesting that interference with these genes expression allows the infected cells to proliferate and/or survive (Wagner, Science, 2014; http://www.sciencemag.org/cgi/content/abstract/science.1256304)

Ongoing projects (R01 AI091550 and R01 AI114348) are focused on understanding whether specific HIV integration events lead to the persistence of HIV DNA that is infectious or defective; use in vitro mutagenesis to determine the effects of specific integration events on cellular function; and on whether during acute HIV infection the antigen specificity of HIV-infected cells that would be targeted for cure in individuals who start ART during this time.

2. Systemic inflammation in HIV-infected individuals: Individuals whose viral replication is suppressed by ART continue to have biomarkers indicative of ongoing diffuse inflammation that accelerates atherosclerosis and cardio- and cerebral-vascular events. Given the timing of HIV acquisition by infected children, substantial morbidity could occur from inflammation despite suppressive ART. We hypothesize that ongoing production of viral RNA or proteins drives inflammation, rather than the alternative hypothesis that immune depletion of gut lymphocytes during acute infection allow bacterial translocation.

An ongoing project (funded by SCRI) aims to determine if low-level production of HIV virions or 16sDNA correlate with immune activation and help develop a short interventional trial to diminish inflammation.

3. HIV Resistance to antiretrovirals: Our group has conducted many studies aimed at better understanding the transmission, selection and persistence of drug-resistant viruses. We have developed economical assays with the goal of making testing accessible to resource-poor communities, to improve the management of HIV infection. Currently, we are conducting a randomized-controlled trial of our oligonucleotide ligation assay (OLA) detection of HIV-drug-resistance pre-ART in Kenya. The primary outcome is the rates of ART-associated suppression of viral replication among subjects randomized to testing or standard-of-care. In addition, we will analyze issues related to transfer of technology and will model the cost-effectiveness of the OLA in ART management. Secondly, with UW bioengineers, we are simplifying this OLA to make a simpler and faster assay.

Ongoing projects (R01 AI100037 and R01 AI110375) aim to better understand the role of specific transmitted mutant codons and define the threshold concentration of mutants that result in virologic failure of ART; to convert our PCR-based assay to an isothermal format; optimize Illumina-based sequencing for use as a clinical assay.

Short Communication: Phylogenetic Evidence of HIV-1 Transmission Between Adult and Adolescent Men Who Have Sex with Men.27762596 AIDS research and human retroviruses, 2017 April : 33(4)318-322 PMCID:PMC5372772

Risk of congenital cytomegalovirus infection among HIV-exposed uninfected infants is not decreased by maternal nelfinavir use during pregnancy.26519647 Journal of medical virology, 2016 June : 88(6)1051-8 PMCID:PMC4818099

Development of a novel codon-specific polymerase chain reaction for the detection of CXCR4-utilizing HIV type 1 subtype B.23343425 AIDS research and human retroviruses, 2013 May : 29(5)814-25 PMCID:PMC3636599

Prevalence of pain and association with psychiatric symptom severity in perinatally HIV-infected children as compared to controls living in HIV-affected households.20401767 AIDS Care, 2010 May : 22(5)640-8 PMCID:PMC3156589

Detection of HIV-1 drug resistance in women following administration of a single dose of nevirapine: comparison of plasma RNA to cellular DNA by consensus sequencing and by oligonucleotide ligation assay.20181911 Journal of Clinical Microbiology, 2010 May : 48(5)1555-61 PMCID:PMC2863880

Association between detection of HIV-1 DNA resistance mutations by a sensitive assay at initiation of antiretroviral therapy and virologic failure.20377404 Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2010 May : 1397-404

Virologic and immunologic correlates with the magnitude of antibody responses to the hepatitis A vaccine in HIV-infected children on highly active antiretroviral treatment.19617848 Journal of acquired immune deficiency syndromes (1999), 2009 Sept. : 17-24

Effectiveness of antenatal group HIV voluntary counseling and testing services in rural India.17563273 AIDS education and prevention : official publication of the International Society for AIDS Education, 2007 June : 19(3)187-97

Immune reconstitution after receipt of highly active antiretroviral therapy in children with advanced or progressive HIV disease and complete or partial viral load response.15962224 The Journal of infectious diseases, 2005 July 15 : 192(2)296-302

A proof-of-concept study of short-cycle intermittent antiretroviral therapy with a once-daily regimen of didanosine, lamivudine, and efavirenz for the treatment of chronic HIV infection.15143462 The Journal of infectious diseases, 2004 June 1 : 189(11)1974-82

Efficacy and toxicity of antiretroviral therapy using 4 or more agents: application of a strategy for antiretroviral management in human immunodeficiency virus-infected children.12038889 Archives of pediatrics and adolescent medicine, 2002 June : 156(6)568-73

The effects of zidovudine in the subset of infants infected with human immunodeficiency virus type-1 (Pediatric AIDS Clinical Trials Group Protocol 076).10356140 The Journal of Pediatrics, 1999 June : 134(6)717-24

HIV-1 dynamics in children.10225229 Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology: Official Publication of the International Retrovirology of Association, 1999 April 15 : 20(5)468-73

Risk of mother-to-infant transmission of HIV-1 is not reduced in CCR5/delta32ccr5 heterozygotes.9402070 Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology: Official Publication of the International Retrovirology of Association, 1997 Dec. 1 : 16(4)243-6

Zidovudine, didanosine, or both as the initial treatment for symptomatic HIV-infected children. AIDS Clinical Trials Group (ACTG) Study 152 Team.9182213 The New England Journal of Medicine, 1997 June 12 : 336(24)1704-12

Analysis of the maternal components of the AIDS clinical trial group 076 zidovudine regimen in the prevention of mother-to-infant transmission of human immunodeficiency virus type 1.9086162 The Journal of Infectious Diseases, 1997 April : 175(4)971-4

Effect of pregnancy and zidovudine therapy on viral load in HIV-1-infected women.9117455 Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology: Official Publication of the International Retrovirology of Association, 1997 March 1 : 14(3)232-6

A search for persistent rubella virus infection in persons with chronic symptoms after rubella and rubella immunization and in patients with juvenile rheumatoid arthritis.8838185 Clinical Infectious Diseases: an official publication of the Infectious Diseases Society of America, 1996 Feb. : 22(2)287-94

Effects of zidovudine use during pregnancy on resistance and vertical transmission of human immunodeficiency virus type 1.7620018 Clinical Infectious Diseases: an official publication of the Infectious Diseases Society of America, 1995 May : 20(5)1321-6

A prospective study of the effects of acyclovir treatment on the HSV-2 lymphoproliferative response of persons with frequently recurring HSV-2 genital infections.2540245 The Journal of Infectious Diseases, 1989 May : 159(5)845-50

Frenkel LM, Bryson YJ. 1987

Ontogeny of phytohemagglutinin-induced gamma interferon by leukocytes of healthy infants and children: evidence for decreased production in infants younger than 2 months of age.3110393 The Journal of Pediatrics, 1987 July : 111(1)97-100

Over the past 20 years, our group has conducted projects in Peru, Thailand, Mozambique, Kenya and South Africa. These studies aimed to better understand the transmission, selection and persistence of drug-resistant viruses and have included collaborations with other UW, national and international investigators. We have developed economical assays with the goal of making testing accessible to resource-poor communities, to improve the management of HIV infection. Currently, our laboratory located within Seattle Children's Research Institute (SCRI) focuses primarily on three topics and collaborates broadly with other UW, national and international investigators. 1. Persistence of HIV infection: A major research focus of our work has been to understand the mechanisms that allow HIV to persist despite effective ART. Our group documented that among ART-treated individuals with plasma HIV RNA consistently below the limits of detection included a subset that demonstrated viral evolution, implying low-level viral replication, although the vast majority demonstrated no evolution (Frenkel, JVI, 2003). We were the first to note that transient low-level viremias, or "blips," during ART were usually comprised of populations of identical env and pol sequences (Tobin, JVI, 2005), suggesting production of clonal virus. Our subsequent studies revealed that populations of identical viral sequences in PBMC and sputum (rich in pulmonary macrophages) increase over a decade of ART (Wagner, JVI, 2013), suggesting that clonal proliferation of cells with provirus sustains HIV infection during suppressive ART. Recently, we have documented that identical env sequences have identical integration sites, providing strong supportive evidence that HIV persistence is at least in part due to cellular proliferation, and with ongoing suppressive ART, that these proviruses are increasingly integrated into genes controlling immune functions, the cell cycle or cancers suggesting that interference with these genes expression allows the infected cells to proliferate and/or survive (Wagner, Science, 2014; http://www.sciencemag.org/cgi/content/abstract/science.1256304) Ongoing projects (R01 AI091550 and R01 AI114348) are focused on understanding whether specific HIV integration events lead to the persistence of HIV DNA that is infectious or defective; use in vitro mutagenesis to determine the effects of specific integration events on cellular function; and on whether during acute HIV infection the antigen specificity of HIV-infected cells that would be targeted for cure in individuals who start ART during this time. 2. Systemic inflammation in HIV-infected individuals: Individuals whose viral replication is suppressed by ART continue to have biomarkers indicative of ongoing diffuse inflammation that accelerates atherosclerosis and cardio- and cerebral-vascular events. Given the timing of HIV acquisition by infected children, substantial morbidity could occur from inflammation despite suppressive ART. We hypothesize that ongoing production of viral RNA or proteins drives inflammation, rather than the alternative hypothesis that immune depletion of gut lymphocytes during acute infection allow bacterial translocation. An ongoing project (funded by SCRI) aims to determine if low-level production of HIV virions or 16sDNA correlate with immune activation and help develop a short interventional trial to diminish inflammation. 3. HIV Resistance to antiretrovirals: Our group has conducted many studies aimed at better understanding the transmission, selection and persistence of drug-resistant viruses. We have developed economical assays with the goal of making testing accessible to resource-poor communities, to improve the management of HIV infection. Currently, we are conducting a randomized-controlled trial of our oligonucleotide ligation assay (OLA) detection of HIV-drug-resistance pre-ART in Kenya. The primary outcome is the rates of ART-associated suppression of viral replication among subjects randomized to testing or standard-of-care. In addition, we will analyze issues related to transfer of technology and will model the cost-effectiveness of the OLA in ART management. Secondly, with UW bioengineers, we are simplifying this OLA to make a simpler and faster assay. Ongoing projects (R01 AI100037 and R01 AI110375) aim to better understand the role of specific transmitted mutant codons and define the threshold concentration of mutants that result in virologic failure of ART; to convert our PCR-based assay to an isothermal format; optimize Illumina-based sequencing for use as a clinical assay.

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